Level 2 (mid-level) evidence
Recommendations for initiation of antiretroviral therapy (ART) in asymptomatic adults with HIV are generally based on CD4 T-cell counts; the level needed to start therapy has been progressively raised over the last decade and favors earlier treatment (N Engl J Med. 2013;368[10]:886-889). While treatment guidelines in the United States recommend antiretroviral therapy for all patients infected with HIV, the evidence to support this recommendation was strongest for starting therapy when CD4 T-cell counts are less than 500 cells/mcL. To address this evidence gap, two recent randomized trials, the START Trial and the TEMPRANO ANRS 12136 Trial, compared immediate initiation of ART to delaying ART until specific clinical criteria have been met in asymptomatic, treatment-naïve patients with HIV infection (N Engl J Med. 2015;373[9]:795-807; N Engl J Med. 2015;373[9]:808-822).
The START trial included 4,685 adults (mean age, 36 years; male, 73%) from 35 countries with CD4 T-cell counts greater than 500 cells/mcL who were randomly assigned to immediate or delayed ART. The protocol for delayed initiation of ART included starting therapy when the patient had a CD4 T-cell count of 350 cells/mcL or less, or the patient developed AIDS or another condition requiring the initiation of ART (such as pregnancy). This trial was terminated early at the recommendation of the data and safety monitoring board after the group receiving immediate ART demonstrated superior outcomes. At a mean follow-up of 3 years, 1.8% of patients in the immediate-therapy group and 4.1% of patients in the delayed-therapy group experienced at least one of the composite outcomes of serious AIDS-related events, serious non-AIDS-related events, or death (p<0.001; number needed to treat [NNT], 44). Serious AIDS-related events, serious non-AIDS-related events, tuberculosis, and Kaposi sarcoma were all significantly reduced in the immediate-initiation group. Of note, the majority of adverse events observed in this trial occurred when the CD4 count was greater than 500 cells/mcL. There were no significant differences between groups in all-cause mortality, grade 4 adverse events (defined as potentially life-threatening events requiring medical intervention not attributable to AIDS), or unscheduled hospitalizations.
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The TEMPRANO trial included 2,056 patients (median age, 35 years; female, 75%) from the Ivory Coast in west Africa with CD4 T-cell counts less than 800 cells/mcL and randomly assigned patients to immediate or delayed initiation of ART and preventative therapy with isoniazid for 6 months or no isoniazid preventative therapy. In this trial, delayed ART initiation was defined by the current World Health Organization (WHO) criteria at the time of enrollment, and patients were followed for 30 months. Comparing immediate to delayed initiation of ART, death or severe HIV-related illness occurred in 6.2% vs. 10.9% of study subjects, respectively (p<0.05; NNT, 22). AIDS, tuberculosis, and invasive bacterial disease were all significantly less common in patients immediately treated with ART, compared to those with delayed initiation of treatment. Grade 3 and 4 adverse events were significantly increased in the immediate-ART group, compared to the delayed-ART group during the first 6 months after randomization. However, this trend was reversed in the 6 to 30 months after randomization and immediate ART was associated with a significantly reduced risk of serious adverse events, compared with delayed ART in this time period.
These two randomized trials demonstrate benefits to mortality and morbidity with ART initiation in HIV-infected patients with CD4 T-cell counts greater than 500 cells/mcL. Although both trials were not blinded and the event rates were relatively low, they show a clear benefit to early initiation of ART in asymptomatic patients with HIV infection. This benefit was also observed without an increase in the rate of serious adverse events. Together, the results of these trials provide clear evidence that immediate initiation of ART reduces the development of AIDS, AIDS-related complications, and death in HIV-infected patients regardless of CD4 T-cell counts.
Based on these results, the US Department of Health and Human Services has now issued a strong recommendation for initiation of ART in all adults with HIV infection, including those with CD4 T-cell counts greater than 500 cells/mcL (Statement by the HHS panel on antiretroviral guidelines for adults and adolescents regarding results from the START and TEMPRANO Trials, https://aidsinfo.nih.gov/news/1592/statement-from-adult-arv-guideline-panel—start-and-temprano-trials).
Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester.
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